Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: B0001 .4
471,332 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The relative ability of arylacetamide deacetylase enzyme systems of dog liver to carry out the deacetylation of the carcinogens, 4-acetylaminobiphenyl, 2-acetylaminofluorene, and 2-acetylaminaphthalene, was examined. The arylacetamides were incubated with unfortified dog liver microsomes, and enzyme activity (nmol arylamine/mg protein/hr) was estimated by colorimetric quantitation of the resulting arylamines. The dog liver enzyme system displayed characteristics similar to those described for the rodent liver enzyme system in that enzyme activity was greatest in liver tissue, was localized in the microsomal subcellular fraction, required no cofactors, and was inhibited by heat, sodium fluoride, and thiol reagents. In five replicate assays, the relative rates of deacetylation were about 10, 6, and 1 with 4-acetylaminobiphenyl (84.8 +/- 12.4), 2-acetylaminofluorene (52.5 +/- 5.1), and 2-acetylaminonaphthalene (8.8 +/- 3.3), respectively. As a canine urinary bladder carcinogen, 4-acetylaminobiphenyl is considered more potent than 2-acetylaminofluroene, while 2-acetylaminonaphthalene is devoid of detectable carcinogenic activity, despite the fact that 2-aminoaphthalene is a well-established canine urinary bladder carcinogen. Removal of the acetyl group may be a requirement for urinary bladder carcinogenesis; accordingly, the present studies demonstrate the appearance of a direct relationship between dog liver deacetylase enzyme specificity and urinary bladder susceptibility to these carcinogenic arylacetamides.
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PMID:Enzymic deacetylation of carcinogenic arylacetamides by tissue microsomes of the dog and other species. 0 50

The two-stage or cocarcinogenic hypothesis of carcinogenesis involves an initiator (carcinogen) and a promotor (cocarcinogen) being utilized in combination to produce more tumors than either would alone. This theory was tested at the cellular level utilizing Tumor Promoting Agent, 12-0-tetradecanoly-phorbol-13-acetate, (promotor) in combination with submaximal and maximal doses of methylnitrosourea (initiator). Tumor promoting agent, which can cause some tumors itself, was found to enhance the activity of guanylate cyclase (E.C.4.6.1.2.), an enzyme that has been associated with normal and abnormal growth. Tumor promoting agent when utilized in combination with submaximal stimulatory doses of methylnitrosourea had an additive effect on guanylate cyclase activity, but the agent had no further additive effect on guanylate cyclase activation when methylnitrosourea was utilized in maximal stimulatory doses. These results indicate a carcinogen acting alone without a promoter can maximally activate guanylate cyclase and would suggest that at the cellular level a promotor is not absolutely necessary for the changes observed morphologically in canerous cells. The promotor, however, did enhance the enzyme's activity when a submaximal dose of the carcinogen was used indicating that promoting agents, at least biochemically, appear capable of potentially contributing to the development of a cancerous cell.
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PMID:Biochemical evidence of cocarcinogenesis: tumor promoting agent enhances methylnitrosourea activation of rat guanylate cyclase activity. 3 62

An epidemiologic study of clear cell vaginal adenocarcinoma in young women (15-22 years old) showed an apparent association with maternal ingestion of diethylstilbestrol (DES) during 1st trimester pregnancy. In 1971, a Registry of Clear Cell Adenocarcinoma of the Genital Tract in Young Females was established, and shortly thereafter the Food and Drug Administration warned that DES and chemically related nonsteroidal estrogens were contraindicated during pregnancy. DES-exposed females have a 0.14 to 1.4/1000 risk of developing adenocarcinoma of the cervix/vagina by age 24. Diagnoses of these cancers usually are made in girls between the age of 14 and 23 years with peak incidence at age 19; data further shows that DES is an incomplete carcinogen and that additional factors contribute to its carcinogenesis. About 20% of DES-exposed women will have a deformity of the upper vagina/cervix, and approximately 95% will have abnormal columnar epithelium on the cervix/upper vagina. 75% of patients whose mothers were exposed to DES in utero during the 8th week of gestation or earlier will have vaginal adenosis; 7% will have this finding if the mother's exposure occurred after the 17th week. Recent reports also indicate a high incidence of abnormalities in the uterus/oviducts associated with gross changes in the upper vagina/cervix. Asymptomatic girls who had DES exposure in uteru should have a complete annual pelvic examination at menarche or by age 14 years. Younger girls who develop abnormal vaginal bleeding/discharge should also have a periodic thorough examination and Pap smear, as well as palpation of the entire length of the vagina/cervix. So far, cervical/vaginal adenocarcinoma has been diagnosed at initial examination, with the ratio of vaginal to cervical adenocarcinoma being almost 2:1. There is no standard therapy yet for adenocarcinoma of young women. Treatment is on a case to case basis, and prognosis depends on the stage of the disease when diagnosed.
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PMID:Congenital diethylstilbestrol-associated vaginal/cervical adenosis (DES babies). 15 73

DNA synthesis in a transplanted hepatoma induced by 3'-methyl-4-dimethylaminoazobenzene was significantly reduced (P less than 0.01) in rats maintained on diets low (0.4 mug/g) or high (greater than or equal to 500 mug/g) in zinc when compared with control animals given 60 mug zinc/g. 3-Methylcholanthrene-induced carcinogenesis was considerably lowered in mice receiving the same low or high zinc diets during the induction periods.
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PMID:Zinc intake, neoplastic DNA synthesis, and chemical carcinogenesis in rats and mice. 16 62

To help understand how intragastric nitrosation forms N-nitroso compounds, nitriet disappearance from the rat stomach was measured after food containing nitrite was given. In preliminary experiments, nitrite disappearance from buffered aqueous solutions became more rapid as the pH was lowered from 5 to 1 and, at a given pH, was more rapid in a slurry of commercial rat food. The disappearance of nitrite from buffer was little affected by the addition of pepsin, mucin, albumin, or rat gastric contents. When starved rats were given 5 g food with 1.82 mg nANO3/g, nitrate was not reduced to nitrite in the stomach. Five g food containing 154 mug NaNO2/g was administered similarly, and the total stomach (T) and glandular and nonglandular parts (G and NG) were analyzed after 1.5 hours. Weight and nitrite concentration of the stomach contents dropped linearly and the amount of nitrite dropped exponentially (with a half-life of 1.4 hr). Mean nitrite concentration in G was less than half that in NG. From similar experiments with phenol red, emptying accounted for 60% of nitrite loss from T. In G, nitrite concentration was reduced about 3 times due to dilution and 3 times due to other causes. Conditions in G, e.g., nitrite concentration, pH, and empyting time, were discussed in relation to carcinogenesis experiments with nitrite plus amines and amides.
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PMID:Disappearance of nitrite from the rat stomach: contribution of emptying and other factors. 23 94

Young adult female rats of either the Sprague-Dawley stock or the ACI strain were each given an implant of a compressed pellet of 5 mg diethylstilbestrol (DES) and 15 mg cholestrol 2 days before irradiation with 0.4, 1.3, or 4.0 rads of 0.43-MeV neutrons. These rats were studied, along with appropriate irradiated and nonirradiated controls, until death or for a maximum of 48 weeks. Response differences between the strain and stock included the following: DES produced both pituitary tumors and mammary adenocarcinomas (MAC) in ACI rats only. Neutron radiation increased mammary fibroadenoma (MFA) formation in Srague-Dawley rats only. No interactions between DES and radiation on MAC formation in Sprague-Dawley rats or MFA formation in ACI rats were demonstrated. However, when DES and neutron radiation were combined, DES appeared to inhibit the MFA response to radiation in Sprague-Dawley rats. In contrast, DES appeared to act synergistically with neutron radiation on MAC formation in ACI rats. These results clearly demonstrate rat differences in mammary gland carcinogenesis in response to estrogen, to radiation, or to a combination of both agents.
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PMID:Rat differences in mammary tumor induction with estrogen and neutron radiation. 28 58

Epidemiologic, clinical and pathologic data on all cases of clear cell adenocarcinoma of the genital tract in women born in 1940 and later are collected by the Registry for Research on Hormonal Transplacental Carcinogenesis. Other cases of genital cancer are also recorded if there is a history of prenatal hormone exposure. Evidence strongly suggest a mullerian nature for clear cell adenocarcinomas. Of the 333 cases accessioned between 1970 and 1976, about 2/3 of the completely investigated cases had histories of prenatal exposure to stilbestrol (DES) or similar compounds. Estimated risk of clear cell adenocarcinoma ranges from 0.14 to 1.4 per 1000 DES-exposed, with age-incidence peaking at age 19. Cytology and a thorough pelvic examination are important tools for accurate diagnosis. Surgery and radiation are used to treat these tumors, but follow up in most cases has been limited to 5 years. Several cases of small or superficial tumors have been observed to spread to regional pelvic nodes, with recurrences in the lungs or supraclavicular areas. For inquiries, contact the Registry for Research on Hormonal Transplacental Carcinogenesis, 5841 S. Maryland Ave., Chicago, Ill 60637. Analysis of pathologic specimens should be directed to Robert E. Scully, MD, Dept of Pathology, Massachusetts General Hospital, Boston, Mass 02114.
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PMID:DES-associated clear cell adenocarcinoma of the vagina and cervix. 52 31

This work confirms the previous observation that a single application of N-hydroxy-2-fluorenylacetamide or N-hydroxy-3-fluorenylacetamide to the mammary gland of the rat induced a high incidence of tumors, whereas the corresponding arylamides, N-2-fluorenylacetamide (2-FAA) and N-3-fluorenylacetamide, were only weakly active. The results suggested N-hydroxylation of the arylamides as a prerequisite for mammary carcinogenesis. Since N-hydroxylation of 2-FAA by hepatic microsomes is catalyzed by the mixed-function oxidase containing cytochrome P-450 or the 2-methylcholanthrene-inducible cytochrome P1-450, we examined whether these cytochromes are present in mammary microsomes. In contrast to liver, neither cytochrome nor N-hydroxylation of 2-FAA was detected in the mammary gland of normal and 3-methylcholanthrene-treated rats. These experiments indicated that the N-hydroxylation of 2-FAA, although obligatory for induction of mammary neoplasia, is not performed in the mammary gland but may take place in the liver. We also examined the carcinogenicity of N-acetoxy-2-fluorenylacetamide and N-acetoxy-3-fluorenylacetamide for the mammary gland upon topical application. Since both acetates were carcinogenic and since the acetyl group of acetyl coenzyme A is transferred to fluorenylhydroxamic acids at pH 7.4, these esters may be ultimate carciogens in mammary carcinogenesis. Ovariectomized rats did not develop mammary tumors after a single application of the fluorenylhydroxamic acids, and administration of estradiol and fluorenylhydroxamic acids to the ovariectomized rats did not improve the tumor yield. These results indicate that induction of mammary tumors by fluorenylhydroxamic acids is under hormonal control.
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PMID:Mammary carcinogenesis in the rat by topical application of fluorenylhydroxamic acids and their acetates. 83 Apr

Tetrakis(hydroxymethyl)phosphonium chloride (THPC) and Pyroset TKP, which is the mixed acetate/phosphate of the same phosphonium base, are widely used in flame-retardant cotton fabrics, particularly in children's sleepwear. THPC degrades thermally and under certain chemical conditions to yield hydrochloric acid and formaldehyde (CH2O). In solution, the latter two compounds are in equilibrium with the known potent carcinogen bis(chloromethyl)ether (BCME). A sample of commercial THPC contained from 4% (at pH 0.4) to 14% (at pH greater than 4.5) free CH2O. The material, as supplied by the manufacter, showed pH 0.4. Gas chromatographic analysis of aqueous commercial THPC did not reveal any peak chracteristic of BCME under conditions where 0.1 ppm of the material can be detected. Application to mouse skin of THPC ( 2 mg in 0.1 ml DMSO) and of Pryset TKP (7 mg in 0.1 ml DMSO), three times per week for 400 days with 20 female ICR/Ha Swiss mice per group, gave one squamous carcinoma in the THPC-treated group. THPC was inactive as an initiating agent in two-stage mouse skin carcinogenesis with phorbol myristate acetate as promoter. Both agents were active as tumor promoters, using a single application of 7,12-dimethylbenz[a]anthracene (20 microng in 0.1 ml acetone) as initiator. With THPC as promoter (2 mg in 0.1 ml DMSO, thrice weekly) 3 of 20 mice bore papillomas which progressed to squamous carcinoma. With Pyroset TKP as promoter (7 mg in 0.1 ml DMSO) 7 of 20 mice bore papillomas of which two progressed to squamous carcinoma.
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PMID:Evaluation of chemical flame retardants for carcinogenic potential. 84 2

A quantitative microbial assay was used to study the stability of known mutagenic and carcinogenic compounds in cell culture medium. Ten direct-acting carcinogens, when incubated in culture medium with 15% fetal bovine serum at pH 7.2-7.4 and 37 degrees C, became inactive at varying rates. Biologic half-lives of the test compounds ranged from 8 minutes to 67 hours. In contrast, six procarcinogens showed no significant inactivation after 3 weeks' incubation. The biologic half-lives of each compound were presented, and the significance of these findings as they relate to cell culture carcinogenesis and mutagenesis assays was discussed.
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PMID:In vitro studies of chemical mutagens and carcinogens. I. Stability studies in cell culture medium. 89 51


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